Our findings establish that functional chimeric kidneys develop from metanephroi transplanted in adult hosts.

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Effects of hepatocyte growth factor (HGF) administration were examined in a model of acute ischemic renal injury induced by bilateral renal artery occlusion in rats. Compared with rats administered vehicle, rats administered 20 micrograms HGF subcutaneously 30 min postischemia had significantly lower serum creatinine and blood urea nitrogen levels over the course of 7 days postocclusion, enhanced insulin clearances measured on day 2 postocclusion, reduced mortality, and much less injury evident by examination of kidney histologies 7 days postinjury. The tubular regeneration that occurred postischemic injury was reflected by increased incorporation of 5-bromo-2'-deoxyuridine (BrdU) in cortical tubular epithelium compared with incorporation in kidneys from noninjured rats. HGF enhanced BrdU incorporation compared with vehicle, indicating enhanced mitogenesis. The weight loss that occurs postischemic injury was not ameliorated by the dose of HGF we employed. We conclude that administration of HGF postischemic injury to rats stimulates the recovery of normal kidney function and the regeneration of proximal tubular epithelium.

Apoptosis of the developing metanephric kidney plays an important role in renal organogenesis. The bcl-2 is an oncogene that inhibits apoptotic cell death in a variety of settings. The bcl-2 (-/-) mice complete embryonic development but, in contrast to bcl-2 (+/-) and bcl-2 (+/+) littermates, manifest growth retardation, hypopigmentation of hair, lymphoid apoptosis, abnormal kidney morphology, and renal failure postnatally. To provide insight into the mechanism for the latter abnormalities, we examined metanephric kidneys from bcl-2 (-/-), bcl-2 (+/-), and bcl-2 (+/+) mice, as well as embryonic day 12 (E12) mouse embryos, and compared growth and development of metanephroi in vitro. Kidneys from bcl-2 (+/-) mice developed normally. In contrast, development of kidneys from bcl-2 (-/-) mice was abnormal as reflected by a marked reduction of renal size in newborns compared with kidneys of bcl-2 (+/-) littermates. In addition, kidneys from bcl-2 (-/-) mice contained far fewer nephrons and had smaller nephrogenic zones. Although metanephroi obtained from E12 bcl-2 (+/-) and bcl-2 (-/-) mouse embryos were comparable in size, apoptosis of cells within metanephric blastemas of metanephroi from E12 bcl-2 (-/-) embryos was strikingly enhanced compared with that in blastemas of metanephroi from bcl-2 (+/-) embryos. During 3 days in culture, growth and development of metanephroi from bcl-2 (-/-) embryos were visibly reduced compared with those from bcl-2 (+/-) embryos.(ABSTRACT TRUNCATED AT 250 WORDS)

The insufficient supply of tissue, loss posttransplantation, and limited potential for expansion of beta-cells restrict the use of islet allotransplantation for diabetes. A way to overcome the supply and expansion problems is to xenotransplant embryonic tissue. We have shown that whole rat pancreatic anlagen isotransplanted into the omentum of rats, or xenotransplanted into costimulatory blocked mice, undergo growth and differentiate into islets surrounded by stoma without exocrine tissue. Isotransplants normalize glucose tolerance in diabetic hosts. Here, we show that embryonic day 29 porcine pancreas transplanted into the omentum of adult diabetic rats undergoes endocrine tissue differentiation over 20 wk and normalizes body weights and glucose tolerance. Unlike rat-to-rodent transplants, individual alpha- and beta-cells engraft without a stromal component, and no immunosuppression is required for pig-to-rat transplants. Herein is described a novel means to effect the xenotransplantation of individual islet cells across a highly disparate barrier.